Medically inoperable peripheral lung cancer treated with stereotactic body radiation therapy.

BACKGROUND: Lung cancer is the most frequent cause of cancer-related death in North America. There is wide variation between patients who are medically inoperable and those managed surgically. The use of stereotactic body radiotherapy (SBRT) has narrowed the gap in survival rates between operative and non-operative management for those with early stage disease. This retrospective study reports outcomes for the treatment of peripheral non-small cell lung carcinoma (NSCLC) with SBRT from a single community practice. METHODS: Sixty-seven consecutive patients (pts) with inoperable, untreated peripheral lung tumors were treated from 2010 through 2012 and included in this study. Stereotactic targeting was facilitated by either spine or lung-based image guidance, either with or without fiducial marker tracking with a frameless robotic radiosurgery system. Peripheral tumors received a median biological effective dose (BED) of 105.6 Gy10 or in terms of a median physical dose, 48 Gy delivered over 4 daily fractions. Survival was measured using the Kaplan-Meier method to determine rates of local control, progression of disease and overall survival. The Cox proportional hazards regression model was used to study the effects of tumor size, stage, histology, patient age, tumor location (lobe), tracking method, and BED on the survival distributions. RESULTS: The median follow-up for this cohort was 24.5 months (range: 2.4-50.3) with an overall (OS) 3-year survival of 62.4 % (95 % CI: 74.3-47.3). The median progression-free survival was 28.5 months (95 % CI: 15.8 months to not reached). Local control (LC), defined as a lack of FDG uptake on PET/CT or the absence of tumor growth was achieved in 60 patients (90.9 %) at the time of first follow-up (median 3 months, range: 1-6). Local control at one year for the entire cohort was 81.8 % (95 % CI, 67.3-90.3). The one-year OS probability among those who achieved local control at first follow-up was 86.2 % (95 % CI, 74.3-92.9) but no patients who did not achieve LC at first follow-up survived one year. Of the 60 pts that achieved initial LC, 16 have died. The rates of local control, progression-free survival and overall survival were not statistically different for patients treated using a fiducial target tracking system versus non-invasive guidance. (p = 0.44, p = 0.97 and p = 0.66, respectively). No National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE-4) grade 3 or greater toxicity was observed. CONCLUSION: SBRT is an effective treatment for medically inoperable NSCLC patients with peripherally located tumors. This therapy appears to be well tolerated with low toxicity, and patient outcomes when using non-invasive tumor tracking systems are not inferior to traditional fiducial-based techniques.

Permanent prostate brachytherapy: a century of technical evolution.

PURPOSE: To summarise the practical aspects of the development of techniques of interstitial permanent prostate brachytherapy (PPB) implantation. Prostate brachytherapy dates back to Pasteau's publication in 1913 describing the insertion of a radium capsule into the prostatic urethra to treat carcinoma of the prostate. Various implantation methods were employed but with unsatisfactory results until the development of the transrectal ultrasound in the 1980s. The subsequent two-stage Seattle technique allowed for a planned homogenous distribution of radioactive sources throughout the gland resulting in biochemical control comparable to surgical and external beam radiotherapy series. With the advent of advanced computer software and improved imaging, the technique has developed accordingly to a single stage procedure with on-table dosimetric assessment. The principles of targeting dose to the prostate while avoiding surrounding organs at risk remain as relevant today as nearly a century ago. There is an array of techniques to consider for the novice PPB provider. Whether the evolution of PPB techniques will translate into improved biochemical control is yet to be seen.

Permanent prostate brachytherapy in men with clinically localised prostate cancer.

Permanent prostate brachytherapy techniques are associated with excellent biochemical control for patients with localised prostate cancer. Ten-year data show that permanent prostate brachytherapy is compatible with external beam irradiation or radical prostatectomy. However, treatment protocols and techniques for prostate brachytherapy vary between centres and there is little conformity of treatment protocols. The selection of patients for monotherapy or combined external beam irradiation and brachytherapy is controversial. The role of neoadjuvant androgen deprivation also remains unanswered in patients with localised prostate cancer. In addition, post-implant dosimetry may in fact be more significant for predicting outcome than the addition of adjuvant therapies, and should be a requirement when performing prostate brachytherapy. Data now seem to support specific computed tomography (CT)-based criteria to evaluate implant quality and delivered dose to the prostate. Unfortunately, prostate oedema and poor imaging techniques are limiting factors for evaluating implant dosimetry. Treatment planning techniques that use new treatment planning computers may assist in improving the implant procedure and dosimetry and are now available.

The role of external radiotherapy in patients treated with permanent prostate brachytherapy.

To examine the difference in Prostate Specific Antigen (PSA)-Relapse Free Survival (RFS) in patients (pts) with prostate cancer treated with permanent prostate brachytherapy (PPB) alone (monotherapy) or combined modality PPB and external radiotherapy (CMT) by a matched pair analysis. There were 1476 pts who were treated loosely based on the American Brachytherapy Society criteria for monotherapy or CMT. PSA-RFS was based upon the Kattan modification of the ASTRO consensus panel definition. A computer generated matching process was undertaken to produce two equally weighted pairs of patients divided by treatment methodology and Kaplan-Meier PSA-RFS curves were generated and compared by chi(2) testing. All pts were treated between 1992 and 2000 with a 6-y PSA-RFS of 81.9%. The median follow-up was 34.7 months. Patients treated with CMT presented with higher pre-treatment PSA values, Gleason sum score, clinical stage, risk classification, and were more likely to be treated with neoadjuvant hormones. A matched-pair analysis with 314 pts in each group was created stratified by the addition of neoadjuvant hormones, Gleason score sum and the pretreatment PSA value. Actuarial 5-y PSA-RFS was 77.0% for the monotherapy group and 81.1% for the combined therapy group (P=0.54).chi(2) testing by pretreatment PSA value, Gleason score sum, risk stratification, isotope and the addition of neoadjuvant hormones failed to identify any group with a significant difference in 5-y PSA-RFS. In conclusion, this retrospective study presents a large cohort of patients treated with PPB that failed to identify a significant advantage for the addition of combined therapy. A matched pair analysis performed also failed to identify any significant difference based on treatment modality.

Pretreatment nomogram for predicting freedom from recurrence after permanent prostate brachytherapy in prostate cancer.

OBJECTIVES: To develop a prognostic nomogram to predict the freedom from recurrence for patients treated with permanent prostate brachytherapy for localized prostate cancer. METHODS: We performed a retrospective analysis of 920 patients treated with permanent prostate brachytherapy between 1992 and 2000. The clinical parameters included clinical stage, biopsy Gleason sum, pretreatment prostate-specific antigen (PSA) value, and administration of external beam radiation. Patients who received neoadjuvant androgen deprivation therapy were excluded. Failure was defined as any post-treatment administration of androgen deprivation, clinical relapse, or biochemical failure, defined as three PSA rises. Patients with fewer than three PSA rises were censored at the time of the first PSA rise. Data from two outside institutions served as validation. RESULTS: A nomogram that predicts the probability of remaining free from biochemical recurrence for 5 years after brachytherapy without adjuvant hormonal therapy was developed using Cox proportional hazards regression analysis. External validation revealed a concordance index of 0.61 to 0.64, and calibration of the nomogram suggested confidence limits of +5% to -30%. CONCLUSIONS: The pretreatment nomogram we developed may be useful to physicians and patients in estimating the probability of successful treatment 5 years after brachytherapy for clinically localized prostate cancer.

Potency after permanent prostate brachytherapy for localized prostate cancer.

PURPOSE: The evaluation of potency preservation after treatment of localized prostate cancer with transperineal permanent prostate brachytherapy (PPB) and the efficacy of sildenafil were studied. METHODS AND MATERIALS: This study comprised 482 patients who were able to maintain an erection suitable for intercourse before treatment from a cohort of 1166 patients with clinically localized prostate cancer treated with PPB. All patients have been followed prospectively, and actuarial analysis was performed to assess potency preservation over time. Patients treated with sildenafil were evaluated as to its efficacy. RESULTS: The median follow-up of this cohort was 34 months (6--92), with a median age of 68 years (47--80). Potency was preserved in 311 of the 482 patients, with a 5-year actuarial potency rate of 52.7%. The 5-year actuarial potency rate for patients treated with PPB as monotherapy was 76%, and, for those treated with combination external beam radiotherapy (EBT) + PPB, 56% (p = 0.08). Patients treated with neoadjuvant androgen deprivation (NAAD) + PPB had a 5-year potency rate of 52%, whereas those with combination EBT + PPB + NAAD had a potency rate of 29% (p = 0.13). Cox regression analysis identified that pretreatment use of NAAD and patient age predicted for impotence (p = 0.0001 and 0.04, respectively). Of 84 patients treated with sildenafil, 52 had a successful outcome (62%). The response to sildenafil was significantly better in those patients not treated with NAAD (p = 0.04). CONCLUSIONS: The actuarial potency rates at 5 years for patients treated with PPB are lower than generally acknowledged, except for those patients treated with PPB as monotherapy. Patients who received sildenafil exhibited improved potency in a majority of cases.

A comprehensive review of CT-based dosimetry parameters and biochemical control in patients treated with permanent prostate brachytherapy.

PURPOSE: The American Brachytherapy Society recommends that postprostate implant dosimetry be performed on all patients undergoing transperineal interstitial permanent prostate brachytherapy (TIPPB) utilizing CT scan clinical target volume reconstructions. This study was undertaken to assess the recommended dosimetry parameters from a large cohort of patients undergoing TIPPB that would predict for PSA relapse-free survival (PSA-RFS). METHODS AND MATERIALS: Seven hundred nineteen consecutive patients with clinical stage T1/T2 adenocarcinoma of the prostate underwent TIPPB using either I-125 or Pd-103. Postimplant dosimetry was performed at 2 to 3 weeks with CT scan 3-dimensional reconstructions obtained on all patients. The D90 and D100 doses (defined as the minimum dose covering 90% and 100% of the prostate volume, respectively) and the V100 (defined as the percent of the prostate receiving 100% of the prescribed dose) were obtained for each patient. Regression analysis was performed on the D90 dose, D100 dose, and V100 to test for cutoff points that would predict for PSA-RFS, defined by a modification of the American Society for Therapeutic Radiology and Oncology consensus panel statement. A cutoff value was found and was subjected to subset analysis to assess for its robustness. Treatment-related factors were tested for their ability to achieve dosimetry at or above the cutoff dose. RESULTS: The median follow-up from this cohort is 30 months (7-71 months) with a 48-month PSA-RFS of 89.5%. A D90 dose-response cutoff value > or =90% of the prescribed dose was identified. Prostate implants with a D90 dose <90% of the prescribed dose had an 80.4% 4-year PSA-RFS, while those with a D90 dose > or =90% of the prescribed dose had a 92.4% 4-year PSA-RFS (p = 0.001). No cutoff value was found for the V100 and D100 dose that predicted for PSA-RFS. Using the cutoff value, the D90 dose at 90% of the prescribed dose, a difference in 4-year PSA-RFS survival was identified for patients treated with I-125 (p = 0.04), Pd-103 (p = 0.01), TIPPB as monotherapy (p = 0.001), the addition of hormone therapy (p = 0.005), and TIPPB without hormone therapy (p = 0.001). The D90 dose was not significant for the group of patients treated with external beam radiotherapy and TIPPB (p = 0.15). The only significant finding from Cox regression analysis to predict for a poor D90 dose (<90% of the prescribed dose) was a CT/TRUS volume ratio >1.5 (p = 0.02). CONCLUSIONS: The American Brachytherapy Society recommends that postimplant CT-based dosimetry be performed for all patients treated with TIPPB. This prospective study identified that the D90 dose > or =90% of the prescribed dose can be used as a factor for predicting PSA-RFS in patients treated with brachytherapy. A dose-response using the D90 dose was observed for several typical clinical treatment variations used in the practice of TIPPB. Using the D90 dose appears to be a satisfactory parameter for predicting outcome in patients treated with TIPPB.

A theoretical derivation of the nomograms for permanent prostate brachytherapy.

This study calculates the required minimum radioactivity to deliver a prescribed dose of radiation to a target using radioisotopes in permanent prostate brachytherapy. Assuming the radioactivity to be in a continuous form, an integral equation--Fredholm equation of the first kind, can be formulated with the radioactivity density used as the variable. The density distribution to produce a uniform volume dose rate is determined using a quadrature method and the radial profile behaves smoothly from the zero radius, and peaks sharply approaching the volume boundary. The density for Pd-103 is about 1.5 times that of I-125 due to its higher spatial attenuation. A nomogram is the relationship between the total activity per unit dose (A) and the dimension of the volume (d). Expressing the nomogram as A=c X dn U/Gy, then (c,n)= [(0.0098, 2.09) I-125] and [(0.031, 2.25) Pd-103]. Compared with the Memorial nomogram, (c,n)=[(0.011,2.2) I-125] and [(0.036,2.56) Pd-103], or that quoted by AAPM TG64, (c,n)=[(0.014,2.05) I-125] and [(0.056,2.22) Pd-103], our calculation determined an average 33% and 35% decrease for I-125, and 89% and 77% decrease for Pd-103, respectively. Two reasons for the extra total activity found in the Memorial and AAPM nomograms are: (a) An imperfect clinical situation limited by the restraints of implant techniques (e.g., use of templates) associated with the presence of adjacent normal organs, and (b) source discretization into seeds. When radioactivity is clumped as discrete seeds, higher activity is needed because of "wastage" in two aspects: (a) Dose cold-spots at intersource spaces, (b) hot-spots around the sources. Thus in theory, use of lower activity seeds will require less total activity to deliver a prescribed dose. Based on our study, Pd-103 delivers a higher therapeutic ratio and a lower integral dose to the patient compared to I-125.

The definition of biochemical failure in patients treated with definitive radiotherapy.

PURPOSE: The American Society for Therapeutic Radiology and Oncology (ASTRO) published a definition for biochemical failure following treatment of prostate cancer. Others have noted difficulties with interpreting this definition and recommended modifications to accommodate special recurrence patterns. We have compared various modifications to the original ASTRO definition on our series of 1213 patients treated with transperineal permanent prostate brachytherapy. METHODS AND MATERIALS: The ASTRO modifications we considered adjusted for (1) early censoring of nonrecurrent patients with rising prostate-specific antigen levels (PSA), (2) cumulative rather than consecutive rises (without a decrease) as evidence of recurrence, (3) both of the above, and (4) waiting 2 years before data analysis. The Kaplan-Meier method was used to compute the effects on recurrence rate for patients treated with and without neoadjuvant hormones. RESULTS: With the original ASTRO definition, freedom from recurrence in our series of men who did not receive neoadjuvant hormones was 83% at 4 years. All of the modifications considered had statistically insignificant effects on freedom from recurrence rates, varying from 80% to 83% at 4 years. Patients treated with neoadjuvant hormones also showed very little sensitivity to the recurrence definition employed. CONCLUSION: Early censoring of equivocal patients and counting cumulative rather than consecutive rises in PSA (without a decrease) had little empiric effect on the ASTRO recurrence rates. However, we favor the addition of both these modifications to the ASTRO definition on conceptual grounds for evaluating patients following any modality (radiation or surgery), whereby a trend over multiple PSA values is used to judge failure.

Permanent prostate brachytherapy: lessons learned, lessons to learn.

Current techniques for permanent prostate brachytherapy are associated with excellent biochemical control in patients with localized prostate cancer. Data now available confirm 5- to 10-year results with this treatment modality that are comparable to those with external-beam irradiation or radical prostatectomy. Nonetheless, treatment protocols and techniques for prostate brachytherapy vary from center to center. Controversy exists regarding the selection of patients for brachytherapy alone or in combination with external-beam irradiation. The role of neoadjuvant androgen deprivation also remains undefined in patients with localized prostate cancer. Matched-pair analysis studies performed at Memorial Sloan-Kettering Cancer Center have examined the role of isotope selection, the addition of external-beam irradiation, and the use of neoadjuvant androgen deprivation. These studies provide insights into the use of permanent brachytherapy in patients with localized prostate cancer. In addition, postimplant dosimetry needs to be a requirement for centers performing seed implants. Data now appear to support specific computed tomography-based criteria to evaluate implant quality and delivered dose to the prostate. Unfortunately, prostate edema and poor imaging techniques limit the evaluation of implant dosimetry. Treatment planning techniques that utilize new imaging modalities, coupled with computerized treatment planning, may help improve the implant procedure and dosimetry.

Rectal complications associated with transperineal interstitial brachytherapy for prostate cancer.

PURPOSE: As transperineal interstitial permanent prostate brachytherapy (TIPPB) grows in acceptance as an option in the treatment of organ-confined prostate cancer, its associated toxicities are being defined. This clinical report documents rectal toxicity from a large cohort of men treated by a single practitioner for adenocarcinoma of the prostate. METHODS AND MATERIALS: Eight hundred twenty-five men were treated from September 1992 to September 1998 with TIPPB. One hundred-forty were treated in conjunction with external beam irradiation (EBRT) and 685 with TIPPB alone. All patients were implanted under real-time ultrasound guidance. No dose-volume histogram analysis was performed for this study. All patients were followed at 5 weeks after the procedure, then every 3-6 months thereafter. Rectal morbidity was graded by a modified RTOG toxicity scale. Therapy to control symptoms was recommended on an individual basis. RESULTS: The median follow-up for the cohort is 48 months. A total of 77 patients (9.4%) reported Grade 1 toxicity at some time following an implant whereas 54 patients (6.6%) reported Grade 2 toxicity. The peak post-TIPPB time for experiencing rectal toxicity was 8 months at which time Grade 1 and 2 rectal toxicity was reported in 9.5% of the patients. This improved over the subsequent months and resolved in all patients by 312 years. Four patients (0.5%) reported Grade 3 rectal toxicity with rectal ulceration identified on colonoscopy at 1 year from implant. Two of the four patients had colonic manipulation in the radiated portion of the colon which subsequently caused it to bleed. None of the patients required blood product transfusion. In 3 of the 4 patients the Grade 3 rectal toxicity has resolved spontaneously and 1 patient continues to heal at the time of this report. No patient required hospitalization or surgical intervention. CONCLUSION: TIPPB is a tolerable and acceptable treatment option when used alone in early-stage, organ-confined adenocarcinoma of the prostate and in conjunction with EBRT in more advanced disease. This clinical report adds to the growing literature regarding the potential morbidity associated with this procedure and indicates that serious rectal injury is rare.

A nomogram to compensate for intraoperative prostate edema during transperineal brachytherapy.

PURPOSE: Prostate edema during and following prostate brachytherapy may have a negative impact on implant dosimetry. The purpose of this study was to assess the magnitude of prostate edema during the operative procedure and to develop a nomogram of isotope activity required for compensation of such intraoperative prostate volume changes. MATERIALS AND METHODS: Twenty-five consecutive patients with early-stage, localized adenocarcinoma of the prostate underwent ultrasound-guided transperineal interstitial permanent prostate brachytherapy with either iodine 125 or palladium 103. Transrectal ultrasound volume studies of the prostate were performed before and during the implant procedure. Computed tomography-based postimplant dosimetry was performed 3-4 weeks after surgery. RESULTS: A median intraoperative prostate volume increase after insertion of applicator needles of 10.4% (range 1.2-32.5%) was identified. A correlation of -0.55 (95% confidence interval -0.78 to -0.19) between the minimum dose covering 90% of the prostate volume (%D90) and the amount of edema was identified. An algorithm and nomogram was developed to calculate the extra isotope activity necessary to compensate for intraoperative edema. CONCLUSIONS: Prostate edema occurs at the time of transperineal needle placement. A negative correlation was found between the amount of edema and dose coverage of the prostate (%D90). Therefore, to cover the prostate volume adequately, additional isotope activity is required when preoperative treatment planning is performed. This nomogram can be used to compensate for such volume changes.